Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium \u3ci\u3eStreptococcus mitis/oralis\u3c/i\u3e: Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model

Streptococcus mitis/oralis is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro– derived daptomycin-resistant (DAP-R) S. mitis/oralis strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental strain, 351. Metabolic changes associated with the transition to this DAP-R phenotype suggested that inhibiting glycolysis could alter DAP susceptibility. In addition, the strong reliance of S. mitis/oralis on glycolysis for energy and biosynthetic intermediates suggested that inhibiting glycolysis would adversely affect growth and biomass accumulation. To test these hypotheses, we used the lactate dehydrogenase inhibitor oxamic acid (OXA) to assess its efficacy against DAP-S S. mitis/oralis strain 351 during DAP exposures in vitro and ex vivo. As expected, OXA was growth inhibitory to S. mitis/oralis in a dose-dependent manner in vitro; however, it did not alter in vitro DAP susceptibility profiles. In contrast, OXA did prevent the emergence of DAP-R in an ex vivo model of simulated endocardial vegetations. These data suggest that metabolic inhibitors directed against this fermentative bacterium with limited metabolic capabilities could enhance killing and potentially forestall the emergence of DAP resistance

Comparative Analysis of Super-Kamiokande and SNO Solar-Neutrino Data and the Photospheric Magnetic Field

We analyze Super-Kamiokande, SNO, and photospheric magnetic-field data for the common time interval, namely the SNO D2O phase. Concerning rotational modulation, the magnetic-field power spectrum shows the strongest peaks at the second and sixth harmonics of the solar synodic rotation frequency [3 nu(rot) and 7 nu(rot)]. The restricted Super-Kamiokande dataset shows strong modulation at the second harmonic. The SNO D2O dataset shows weak modulation at that frequency, but strong modulation in the sixth-harmonic frequency band. We estimate the significance level of the correspondence of the Super-Kamiokande second-harmonic peak with the corresponding magnetic-field peak to be 0.0004, and the significance level of the correspondence of the SNO D2O sixth-harmonic peak with the corresponding magnetic-field peak to be 0.009. By estimating the amplitude of the modulation of the solar neutrino flux at the second harmonic from the restricted Super-Kamiokande dataset, we find that the weak power at that frequency in the SNO D2O power spectrum is not particularly surprising. Concerning 9.43 yr-1, we find no peak at this frequency in the power spectrum formed from the restricted Super-Kamiokande dataset, so it is no surprise that this peak does not show up in the SNO D2O dataset, either.Comment: 32 pages, 8 tables, 16 figure

Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection

The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P \u3c 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P \u3c 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P \u3c 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity

An integrated neuromechanical model of the mouse to study neural control of locomotion

The 11th International Symposium on Adaptive Motion of Animals and Machines. Kobe University, Japan. 2023-06-06/09. Adaptive Motion of Animals and Machines Organizing Committee.Poster Session P7

Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs

Staphylococcus aureus suggest the use of alternative agents when vancomycin MIC values are ≥2 mg/L. This study examines the outcome of patients treated with daptomycin for S. aureus infections with documented vancomycin MICs. Patients and methods: All patients with skin, bacteraemia and endocarditis infections due to S. aureus with vancomycin MIC values in CORE 2005–08, a retrospective, multicentre, observational registry, were studied. The outcome (cure, improved, failure or non-evaluable) was the investigator assessment at the end of dapto-mycin therapy. Success was defined as cure or improved. Results: Five hundred and forty-seven clinically evaluable patients were identified with discrete vancomycin MIC values [MIC,2 mg/L: 451 (82%); MIC ≥2 mg/L: 96 (18%)]. The vancomycin MIC groups were well matched for patient characteristics, types of infections, first-line daptomycin use (19%) and prior vancomycin use (58%). Clinical success was reported in 94 % of patients. No differences were detected in the daptomycin success rate by the vancomycin MIC group overall or by the infection type. A multivariate logistic regression also failed to identify vancomycin MIC as a predictor of daptomycin failure. Adverse event (AE) rates were not differ-ent when analysed by MIC group; both groups had 17 % of patients with one AE. Conclusions: In this diverse population, daptomycin was associated with similar outcomes for patients, regard-less of whether the vancomycin MIC was categorized as,2 or ≥2 mg/L. Further studies are warranted

Weight-based antibiotic dosing in a real-world European study of complicated skin and soft-tissue infections due to methicillin-resistant <i>Staphylococcus aureus</i>

AbstractWe aimed to characterize real-world dosing of weight-based intravenous (IV) antibiotic therapy in patients hospitalized for methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTIs). This was a subgroup analysis of a retrospective chart review that captured data from 12 European countries. The study included patients ≥18 years old, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Patients treated with IV vancomycin, teicoplanin or daptomycin at any stage during hospitalization were included in this analysis. Analyses were conducted at the regimen level (dosing in mg/kg or in mg, frequency, and total daily dose (TDD)), with potentially multiple regimens per patient, and the patient level, categorizing patients into low, standard (labelled) and high dosing groups according to their initial MRSA-targeted regimen. Among the 1502 patients in the parent study, 998 patients contributed a total of 1050 daptomycin, teicoplanin or vancomycin regimens. Across all regimens, the mean initial TDDs were 6.3 ± 1.9 mg/kg for daptomycin, 10.5 ± 4.9 mg/kg for teicoplanin and 28.5 ± 11.5 mg/kg for vancomycin. A total of 789 patients received first-line therapy with one of the above antibiotics. The majority of patients receiving first-line teicoplanin and daptomycin (96% and 80%, respectively) received higher than labelled cSSTI doses, whereas vancomycin doses were lower than labelled doses in >40% of patients. These real-world data reveal significant deviation from labelled antibiotic dosing in 12 European countries and the potential for suboptimal outcomes in patients with MRSA cSSTIs

Real-world Multicenter Analysis of Clinical Outcomes and Safety of Meropenem-Vaborbactam in Patients Treated for Serious Gram-Negative Bacterial Infections

Fourty patients were treated with meropenem-vaborbactam (MEV) for serious Gram-negative bacterial (GNB) infections. Carbapenem-resistant Enterobacteriaceae (CRE) comprised 80.0% of all GNB infections. Clinical success occurred in 70.0% of patients. Mortality and recurrence at 30 days were 7.5% and 12.5%, respectively. One patient experienced a probable rash due to MEV

Opinion dynamics: models, extensions and external effects

Recently, social phenomena have received a lot of attention not only from social scientists, but also from physicists, mathematicians and computer scientists, in the emerging interdisciplinary field of complex system science. Opinion dynamics is one of the processes studied, since opinions are the drivers of human behaviour, and play a crucial role in many global challenges that our complex world and societies are facing: global financial crises, global pandemics, growth of cities, urbanisation and migration patterns, and last but not least important, climate change and environmental sustainability and protection. Opinion formation is a complex process affected by the interplay of different elements, including the individual predisposition, the influence of positive and negative peer interaction (social networks playing a crucial role in this respect), the information each individual is exposed to, and many others. Several models inspired from those in use in physics have been developed to encompass many of these elements, and to allow for the identification of the mechanisms involved in the opinion formation process and the understanding of their role, with the practical aim of simulating opinion formation and spreading under various conditions. These modelling schemes range from binary simple models such as the voter model, to multi-dimensional continuous approaches. Here, we provide a review of recent methods, focusing on models employing both peer interaction and external information, and emphasising the role that less studied mechanisms, such as disagreement, has in driving the opinion dynamics. [...]Comment: 42 pages, 6 figure